Steroid compounds



United States Patent 2,990,416 STEROID COMPOUNDS Raymond L. Pederson, Kalamazoo, and John C. B'ahcock, Portage Township, Kalamazoo County, 'Mi'ch., assign'ors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Filed June 2, 1958, SenNo. 738,941 4 Claims. (Cl. 260397.45)

The present invention relates to new steroids and is more particularly concerned with 4,17u-dialkyl-11-oxygenated testosterones, the corresponding l-dehydro compounds, and 4,17u-dialkyl-11oxygenated- 17B-hydroxyandrostan-3-0nes, intermediates in the production thereof and methods for the production thereof.

Novel steroids included in this invention and the process for the production therefor are represented by the following sequence of formulae:

(0 i)n' l CH3 CH3 OH OH L.-. I.

CH OHa 0- g H alkyl alkyl ,L (In) CH CH3 OH EH1 ""R ---R O of OH OH 1 all ryl alky (IV) (II) CH3 CH3 OH (RH LW o refi] OH OH O- 3 O- wherein R is an aliphatic hydrocarbon radical containing from one to six carbon atoms, inclusive, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, ocmethallyl, and the like; n and n are whole numbers from one to two, inclusive, R is an oc-hYdIOXY group or a ,6- hydroxy group, and wherein alky'l is a lower-alkyl radical containing from one to four carbon atoms, inclusive.

The 17-substituent, designated as R in the formulae of the foregoing reaction scheme, is referred to in this application as alkyl. It is to be understood that the substituent has the value given hereinabove, i.e., an aliphatic hydrocarbon radical containing from one to six carbon atoms, inclusive, except in Formulae HI and IV, wherein the value of R is that of an alkyl radical of the same chain length. This slight variation is because the compounds of Formulae III and IV are produced by hydrogenation means which saturate any unsaturated aliphatic R substituent as well as the A ring of the compounds.

The novel 4,17a-dialkyl-ll-oxygenated testosterones and 4,17u-dialkyl-l l-oxygenated-il 7B-hydroxyandrostan- 3-ones of the present invention are useful as anabolic and androgenic agents with improved therapeutic ratio, protgestational, anti-estrogenic, central nervous system regulating, gonadotropin inhibiting, steroid potentiating, uterine relaxant, and water and mineral regulating agents. The compounds of the present invention are particularly useful as anabolic agents and possess especial advantage, owing to their favorable anabolic-androgenic ratio, Where clinical efiicacy requires low relative androgenic activity.

For example, 4,17a-dirnethyl-1IB-hydroxytestosterone was found to have an oral anabolic activity of 61 percent of methyltestosterone and an androgenic activity of 8.6 percent of methyltestosterone, thus giving a favorable oral anabolic to androgenic ratio of 7:1. Parental-ally, 4,171 dimethyl 11,8 hydroxytestosterone was found to have an anabolic activity of twenty percent of testosterone propionate with no detectable androgenic properties. Similarly, 4fi,17a-dimethyl-l 1,8,17/3-dihydroxyandrostan- 3-one was found to have an oral anabolic activity of 25 percent of methyltestosterone with no detectable androgenic potency.

It can be readily seen that the anabolic-androgenic ratios of 4,17a-dimethyl-1I/B-hydroxytestosterone, and 4B,- 17u-dimethyl-115,17fi-dihydroxyandrostan-3-one are considerably greater than that for methyltestosterone or testosterone propionate. Thus, when androgenic side effects are the limiting factor, a greater anabolic response can be obtained from 4,17a-dimethyl-ldfi-hydroxytestosterone, or 4B,17o-dimethyl-115,1713-dihydroxyandrostan- 3-one than from methyltestosterone or testosterone propionate at equivalent androgenic doses. This is particularly significant in pediatric and geriatric practice where appreciable androgenic effects are contraindicated.

The compounds of the present invention by virtue of their anabolic properties are useful in promoting retention of nitrogen (protein), increasing Weight, restoring muscle strength, and increasing the sense of well being in debilitated patients. Their ability to increase erythropoiesis, as Well, make them particularly useful in anemic conditions. The compounds of this invention, because of their favorable anabolic-androgenic ratio and high potency at suitable low doses, can effect these responses while producing no, or only a minimal androgenic response. The ability of these compounds to cause gain in weight gives to them the additional utility of being valuable additives to animal and poultry feeds.

The novel compounds of the present invention have decided advantage over many of the selective anabolicandrogenic compounds known in the prior art in that they are active when administered orally.

The compounds of the present invention also possess utility as starting materials for the preparation of the and the like ture with other coacting compounds. ciated with a carrier which can be a solid material or a 3 corresponding l-dehydro compounds. These compounds can be produced by microbiological dehydrogenation of a 4,17ot-dialkyl-1l-oxygenated testosterone, represented by Formulae I and II, such as for'example 4-isopropyl-17oc-buty1-l lfi-hydroxytestosterone,

4-methyl-l7vt- (a-methallyl) -1 l p3-hydroxytestosterone, 4-butyl-l7a-pentyl-l lu-hydroxytestosterone,

and the like with Septomyxa afiz'nis, A.T.C.C. 6737, following the fermentation conditions disclosed in U.S. Patent 2,602,769 to give the corresponding l-dehydro compounds of 4,l7a-dialkyl-ll-oxygenated testosterone, represented by Formulae V and VI, such as for example,

1-dehydro-4,17u-dimethyl-1 1 m-hYdIOXYtBStO sterone, 1-dehydro-4, l7a-dimethyl-l l fi-hydroxytestosterone,

. 1-dehydro-4, 17a-dirnethy1-1 l-ketotestosterone,

1-dehydro-4-methyl-l7a-ethyl-l lot-hydroxytestosterone, 1-dehydro-4-methyl-l 70t-ethY1-1 l B-hydroxytestosterone, 1-dehydro-4-methyl-17a-ethyl-1l-ketotestosterone,

' l-dehydro-4-ethyll7a-propyl-1l-ketotestosterone,

1-dehydro-4-isopropyl-17u-butyl-1 1 ,fi-hydroxytestosterone,

1-dehydro-4-methyl-17a-(a-methallyl)-1 1 ,B-hydroxytestosterone,

1-dehydro-4-butyl-l7a-pentyl-l la-hydroxytestosterone,

The l-dehydro compounds of this invention, represented by Formulae V and VI, can also be produced by dehydrogenation'with selenium dioxode. For'example,

4,17u-dialkyl-1l-oxygenated testosterones, represented by Formulae I and II, such as 4,17a-dimethyll 1 u-hydroxytestosterone 4,17a-dimethyl-l l fi-hydroxytestosterone, 4, 17a-dimethyl-1 l-ketotestosterone,

4,17q-diethyl-l 1 ,B-hydroxytestosterone, 4-methyl- 17 a-ethyl- 1 la-hydroxytestosterone, 4-methyl- 17a-isopropyl- 1 l-ketotestosterone,

4-butyl-l7wpentyl-1 lfi-hydroxytestosterone,

4-methyl-l 7u-( a-m eth allyl) 1 1a-hydroxytestosterone,

: 4-ethyl-l7au-methallyl) -l l-ketotestosterone,

and the like, can be treated with selenium dioxide, as described in Example 6, to produce the corresponding l-dehydro compounds of Formulae V and VI, as disclosed above for l-dehydrogenation with Septomyxa.

" The novel l-dehydro compounds thus produced have gonadotropin inhibiting, progestational, anti-estrogenic, steroid potentiating, anabolic, central nervous system depressant, uterine relaxant, and water and mineral regulating properties.

The novel compounds of this invention can be prepared and administered to the animal organism in a wide variety of oral or parenteral dosage forms singly, or in admix- They can be assoliquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills, or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixirs.

The process of the present invention comprises: treating 17a-alkyl-llot-hydroxytestosterone, or l7 x.-alkyl-l1B- hydroxytestosterone with a secondary cyclic amine to produce the corresponding 3-enarnine. The selected 3-enamine thus produced is then allowed to react with an 'alkylating agent to produce the corresponding 3-enamine -of 4',17 x-'dialkyl-1la-hydroxytestosterone and 4,17ixdi- 4 alkyl-llp-hydroxytestosterone, which on hydrolytic removal of the enamine yields 4,17a-dialkyl-11u-hydroxytestosterone, and 4,17a-dialkyl-llfl-hydroxytestosterone, respectively, represented by Formula I. The 4,17oc-dialkyl-lla-hydroxytestosterone, or 4,17a-dialky1-11fl-hydroxytestosterone thus produced can be oxidized with an oxidizing agent, such as chromic acid or the like to produce the corresponding 4,17u-dialkyl-1l-ketotestosterone represented by Formula II.

Catalytic reduction of 4,17 u-dialkyl-llwhydroxytestosterone, 4,17a-dialkyl-1lfi-hydroxytestosterone and 4,170:- dialkyl-ll-ketotestosterone, represented by Formulae I and II, respectively, using a suitable catalyst, such as palladium on charcoal, or the like, yields the corresponding 45,170; dialkyl 11:1,17/3 dihydroxyandrostan-3-one, 4,8, 17u-dialkyl-11,9,l7B-dihydroxyandrostan-3-one, and 4B, 170:. dialkyl 17B hydroxyandrostane-3,ll-dione, represented by Formulae III and IV, respectively. The 4,8, 170:. dialkyl 17,8 hydroxyandrostane-3,l l-dione represented by Formula IV is also produced by oxidation of 4;9,17u-dialkyl-11p,17/3-dihydroxyandrostan-3-one or 4 8, 17oz dialkyl 11oz,17fl dihydroxyandrostau-B-one represented by Formula HI, using a suitable oxidizing agent, such as chromic acid and the like. The 4p-epimers thus produced can be converted by epimerization with a hydrogen halide, a mineral acid or a base to produce the corresponding 4u-epimers, 4a,17a-dialky1-11a,17fi-dihydroxyandrostan-3-one, 4a,17ot-dialkyl-115,17fl-dihydroxyandrostan-S-one and 4a,17u-dialkyl-17B-hydroxyandrostane-3,l1-dione, represented by Formulae HI and IV, respectively. I

The starting materialsfor the present invention can be prepared from 17a-a1kyl-1l-ketotestosterone and llfi-hydroxy-4-androstene-3,17-dione in accordance with the processes of U.S. Patent 2,735,854 by using the appropriate aliphatic Grignard reagent in the process disclosed in said patent. Illustrative of the starting materials for this invention are 17 a-methyl-l 1 fi-hydroxytestosterone,

17 u-ethyl-l lfl-hydroxytestosterone, 17a-propyl-1 1 B-hydroxytestosterone,

17 m-isobutyll lfi-hydroxytestostero ne, 17a-hexyl-1 lfi-hydroxytestosterone, 17oc-(ot-II1EthflllYl) -1 1 B-hydroxytestosterone,

and the .like. Similarly, substituting 11u-hydroxy-4-androstene-3,17-dione in place of -hydroxy-4-androstene- 3,17-dione, the process disclosed in U.S. Patent 2,735,854 is productive of the corresponding lla-hydroxy compounds, such as for example, 17ot-methyl-1lot-hydroxytestosterone, l7u-ethyl-llu-hydroxytestosterone, l7apropyl l1 a-hydroxytestosterone, 17 a-( a-methallyl) -1 lm-hydroxytestosterone, and the like.

According to the process of the present invention, the ketone group at the 3-position of the starting material is converted to the corresponding 3-enamine derivative by reaction with a secondary cyclic amine. The enamine formation can be carried out in accordance with the disclosure of U.S. Patent 2,781,342. Amines which can be used are pyrrolidine, morpholine, homomorpholine, piperidine, C-alkyl substituted pyrrolidines, e.g., 2,4-dirnthylpyrrolidine, 3-isopropylpyrrolidine, 3,3-dimethylpyrrolidine and the like. The preferred secondary amine is usually pyrrolidine. The selected amine is usually used in a molar excess, calculated on the starting steroid, to achieve the optimum yield of enamine product. Although large molar equivalent excesses of the amine can be employed in the reaction, the preferred proportion of amine to starting' steroid is usually from about 1.1 to seven moles of amine per mole of steroid and especially from about 1.1 to two.

Moisture in the reaction is somewhat detrimental to the procurement of high yields of product, and preferred reaction couditionstherefore include removal of the water formed during the enamine formation by known methods. The reaction is preferably conducted above room temperature, i.e., above about degrees centigrade, e.g., between about 25 and 150 degrees centigrade. Reaction times can vary between about a few minutes to several days, depending in part upon the reaction solvent or solvents, ratio of reactants, selected amine, water removal and temperature.

Reaction solvents employed are benzene, toluene, xylene, chlorobenzene, pentane, hexane, methylene chloride, carbon tetrachloride, methanol, ethanol, tertiary butyl alcohol, tetrahydrofuran, dioxane, and the like.

The 3-enamine of the corresponding starting material thus produced is then alkylated in a dry inert organic solvent such as ethanol, methanol, isopropanol, butanol, ethyl acetate, chlorinated hydrocarbons, and the like with an excess of alkylating agent such as an alkyl halide to produce the 4-alkyl-3-enamine of the corresponding starting material. Alkyl halides thus employed are preferably those wherein the alkyl group has from one to four carbon atoms, inclusive, and the halogen is chlorine, bro mine or iodine with bromine and iodine generally preferred. Representative alkyl halides include methyl, ethyl, propyl, isopropyl, butyl, isobutyl bromide and iodide and allyl bromide. The corresponding alkyl chlorides are also operative, but usually give somewhat inferior yields.

A preferred method is to treat the isolated and dried 3-enamine with an excess of methyl iodide in dry methanol and heat under reflux until the reaction is complete. At the end of the reflux period, the excess alkyl iodide is removed by distillation.

The 3-enamines of 4,17a-dialkyl-1lB-hydroxytestosterone or 4,17a-dialkyl-1lu-hydroxytestosterone thus produced can then be hydrolyzed with water, aqueous acid or base, or alkanol water mixtures. This treatment removes the B-enamine group and results in regeneration of the A -3-keto group in the steroid nucleus with production of the 4-a1kyl derivative of the corresponding starting material.

A preferred method for the hydrolysis of the S-enamine group is in a methanol-water solution containing from one to three percent sodium hydroxide, inclusive. The solution is heated under reflux for two hours and then concentrated by distillation at atmospheric pressure to remove most of the methanol present. The hydrolysis mixture is then diluted with water and extracted with ether, methylene chloride, benzene, toluene, hexane, or the like. The combined solvent extracts are then dried and the solvent removed by distillation giving the 4-alkyl derivative of the corresponding starting material. Illustrative of the compounds that can be prepared from the abovementioned starting materials and shown in the above sequence of formulae as compounds of Formula I, are

4,17a-dimethyl-1 lfi-hydroxytestosterone, 4,17a-dimethyl-1 lot-hydroxytestosterone, 4-methyl-17a-ethyl-1 IB-hydroxytestosterone, 4-methyl-17a-ethyl-1 lot-hydroxytestosterone, 4,l7 x-diethyl-1 l ,B-hydroxytestosterone, 4,17a-diethyl-1 la-hydroxytestosterone, 4-ethyl-17u-propyl-1 1 fi-hydroxytestosterone, 4-propyl-17ot-isobuty1-1 la-hydroxytestosterone, 4-isopropyl-17a-buty1-1 1 B-hydroxytestosterone, 4-butyl-l7a-l1exyl-1 la-hydroxytestosterone, 4-methy1-17a-(a-metha1lyl) -1 1 a-hydroxytestosterone, 4-methyl-l7 mu-methallyl) -1 l B-hydroxytestosterone, and the like.

The resulting products can be purified by conventional procedures such as recrystallization or chromatography, or both.

The above-prepared 4-alky1-l1B-hydroxy steroids and 4-alky1-11a-hydroxy steroids of Formula I can be oxidized to produce the corresponding 4-alky1-11-keto steroids of Formula II. The oxidation can be carried out by a variety of methods, such as for example, by oxidizing the said 4-alkyl-11B-hydroxy steroids or 4-alkyl-1la-hydroxy steroids in acetic acid solution with chromium trioxide, using molar quantities or a slight excess, such as from ten to thirty percent excess, or by oxidizing with a haloamide or imide of an acid, such as N-bromoacetamide, N-chlorosuccinimide, or N-bromosuccinimide dissolved in pyridine, dioxane, or other suitable solvents. At the conclusion of the desired oxidation reaction, the oxidant is generally destroyed by addition of methyl alcohol, ethyl alcohol, and the like, for the chromic acid oxidant or a bisulfite for N-bromoacetamide, N-bromosuccinimide and other N-halo acyl amides and imides. Thereafter the resulting 4-alkyl-11-keto steroids are recovered by conventional means such as by precipitation with water or extraction with water-immiscible solvents, e.g., methylene chloride, ether, benzene, toluene, hexane, and the like, after which the solvent is then removed by distillation. The resulting product can be purified by recrystallization, chromatography, or both, yielding the 4,17oc-dlalkyl-ll-keto steroids represented by Formula II of the above sequence of formulae. Illustrative of the compounds thus produced are 4,17m-dimethyl-1 l-ketotestosterone, 4-methyl-17oc-ethyl-1l-ketotestosterone, 4,17a-diethyl-1l-ketotestosterone, 4-ethyl-17a-propyl-1 l-ketotestosterone, 4-propyl-17a-isobutyl-1l-ketotestosterone, 4-isopropyl-17a-butyl-1 l-ketotestosterone, 4-butyl-17a-hexyl-1 l-ketotestosterone, 4-methyl-1 71xa-methallyl) -l l-ketotestosterone,

and the like.

The 4-alkyl-1la-hydroxy, 4-alkyl-llfi-hydroxy and 4- alkyl-l l-keto steroids, represented by Formulae I and II, respectively, can be saturated by hydrogenating the A double bond in the steroid nucleus. The hydrogenation of the A -steroids can be carried out in the presence of a hydrogenation catalyst, such as palladium supported on charcoal, barium sulfate, zinc oxide, calcium carbonate, mercury salts, and the like, or mixtures thereof palladium on charcoal being preferred. The reaction is usually carried out in a solvent medium; alkanols, hexane, acetone, methyl ethyl ketone, dioxane, acetic acid, or the like organic solvent can be advantageously employed. Of these, tertiary butyl alcohol and percent ethanol are preferred. The catalyst can be saturated with hydrogen prior to the introduction of the 4-alkyl-A -steroid or, preferably the steroid, catalyst and supporting media can be contacted together in a solvent medium prior to introduction of the hydrogen.

It is not necessary to conduct the hydrogenation under pressure, although, when pressure is utilized, a hydrogen gauge pressure of about one to pounds or more is operative, and a pressure of from about ten to 25 pounds is preferred. Any suitable temperature between about zero and 100 degrees centigrade can be employed, with room temperature being satisfactory. Hydrogenation is continued until approximately one molar equivalent of hydrogen has been absorbed. The catalyst is then separated from the solution by filtration and the hydrogenated products recovered by conventional separation or extraction procedures. The hydrogenated product can be purified chromatographically or by recrystallization from organic solvents or mixtures of the same conventionally used for the separation of steroids, thus yielding the corresponding 4,5-dihydro steroids of Formulae III and IV in the above sequence of formulae. Illustrative of the compounds thus produced are 419, 1 7a-dimethyl-l 1a,17B-dihydroxyandrostan-3-one,

4fi-methyl- 17 u-diethyl-1 1 oz, 17 fi-dihydroxy androstan-3 -one,

4 8,17a-diethyl-1 1a, 17fi-dihydroxyandrostan-3-one,

4fi-ethyl-l7u-propyl-l 1a,17(3-dihydroxyandrostan-3-one,

4B-propyl- 17 a-isobutyl 1 10:,175 dihydroxyandrostan-3- one,

pyrrolidyl enamine of 17ot-methyl-1IB-hydroxytestosterone melting at 175 to 179 degrees centigrade with decomposition.

A solution containing eleven grams of the 3-pyrrolidyl enamine of 17ot-methyl-1lfi-hydroxytestosterone in 200 milliliters of dry methanol and 35 milliliters of methyl iodide was heated under reflux for a period of seventeen hours. The solution was concentrated by distillation to about 175 milliliters to remove the excess methyl iodide and then thirty milliliters of ten percent sodium hydroxide was added. The alkaline solution was heated at reflux for a period of two hours, and then concentrated by distillation to about fifty milliliters to remove most of the methanol. Then 100 milliliters of water was added and the reaction mixture was extracted successively with three 100-milliliter portions of methylene chloride. The combined extracts were washed with water, dried over sodium sulfate and concentrated to give 8.1 grams of a syrup. The syrup was dissolved in seventy milliliters of methylene chloride and diluted with 105 milliliters of Skellysolve B giving a precipitate which was removed by filtration. The mother liquor was chromatographed on 160 grams of synthetic magnesium silicate and eluted with acetone-Skellysolve B hexane mixture (180-milliliter fractions) as follows:

Fractions 1-21 7:93 acetone-Skellysolve B hexane Fractions 22-50 10:90 acetone-Skellysolve B hexane The contents of fractions 35-44 exhibited ultraviolet absorption maxima between 249 and 252 m and were combined to give one gram of 4,17ot-dimethyl-1lfl-hydroxytestosterone (I). Recrystallization from acetone gave 0.62 gram of an analytical sample melting at 219 to 221 degrees centigrade and having a rotation of [ab plus 120 degrees (chloroform). The ultraviolet absorption was xgg-, 253 m ti 15,325 Analysis.-Calculated for C H O C, 75.86; H, 9.70. Found: C, 75.90; H, 9.39.

Substituting as starting material other 17ot-alkyl-11B- hydroxytestosterones and 17a-alkyl-11ot-hydroxytestoster ones, such as for example,

17u-ethyl-1 1 B-hydroxytestosterone, 17ot-propyl-1-1 ,B-hydroxytestosterone, l7a-buty1-1 1 B-hydroxytestosterone, 17a-isobutyl-1 1 fl-hydroxytestosterone, 17a-hexyl-1 1 ,B-hydroxytestosterone, l7oc-(0t-I1l6th3llYl) -1 1 fi-hydroxy-testosterone, l7tz-methyl-1 1 u-hydroxytestosterone, 17a-ethyl-1 1 ot-hydroxytestosterone,

17ot-p ropyl-l 1 ot-hydroxytmtosterone, l7a-blltYl-1 la-hydroxytestosterone,

1 7a-pentyl-1 1 OC'hYdI'QXYteStO sterone,

17aot-methallyl) -1 ltt-hydroxytestosterone,

and using methyl iodide or other alkyl halides containing from one to four carbon atoms, inclusive, in place thereof, such as for example, ethyl bromide, propyl chloride, isopropyl iodide, butyl bromide, isobutyl iodide, tertiary butyl chloride, and the like in Example 1 above is productive of 4,17x-dialkyl-1lfi-hydroxytestosterones and 4,170!.- dialkyl-llot-hydroxytestosterones represented by Formula I of this invention, such as 4-methyl-17a-ethyl-1 1 fi-hydroxytestosterone, 4,17tX-d-i6thYl-1 1 fl-hydroxytestosterone, 4-ethyl-17a-propyl-1 1 li-hydroxytestosterone, 4-propyl-17u-isobutyl-1 lfi-hydroxytestosterone, 4-isopropyl-l7a-butyl-1 1 ,B-hydroxytestosterone, 4-butyl-17a-hexy11 1 fi hydroxytestosterone, 4-Il'1thyl-1706-( u-methallyl -1 1 fl-hydroxytestosterone, 4-17a-dimethyl-1 la-hydroxytestosterone, 4-methyl-17wethyl- 1 lot-hydroxytestosterone,

4,17 a-diethyl- 1 lot-hydroxytestosterone,

1 0 4-ethyl- 17a-propyl- 1 1 ot-hydroxytestosterone, 4-isobutyl-1 7 ot-pentyl-1 1 a-hydroxytestosterone, 4 methyl-17aa-methallyl -1 1 ot-hydroxytestosterone,

and the like.

EXAMPLE 2 4,1 7ot-dimethyl-1 1 -ketotest0sterone (II) A solution is prepared containing 0.5 gram or 4,17adimethyl-llfl-hydroxytestosterone (I), 0.15 gram of chromium trioxide, ten milliliters of glacial acetic acid and one-half milliliter of Water. This mixture is stirred and maintained at room temperature for eight hours. Thereafter, excess oxidant is destroyed by the addition of methanol and the mixture is poured into fifty milliliters of ice water and the thus-obtained precipitate collected on a filter and recrystallized three times from ethyl acetate and Skellysolve B hexanes to give 4,17ot-dimethylll-ketotestosterone, a light colored crystalline solid.

In the same manner other 4,17a-dialkyl-1LB-hydroxytestosterones and 4,17ot-dialkyl-1lot-hydroxytestosterones represented by Formula I, such as for example,

4-methyl- 17a-ethyl- 1 lfi-hydroxytestosterone, 4,17a-diethyl-1 1 a-hydroxytestosterone,

4-ethyl- 17 Ot-PI'OPYl-l 1 a-hydroxytestosterone, 4-propyl-17a-isobutyl-1 IB-hydroxytestosterone, 4-isopropyl-17a-butyl-1 1 fl-hydroxytestosterone, 4-butyl-17a-hexyl-1 1/3-hydroxytestosterone, and 4-methyl- 17aet-methallyl-l 1 B-hydroxytestosterone,

when oxidized with chromium trioxide in acetic acid are productive of the other 4,17a-dialkyl-11-keto steroids of Formula II, such as for example, 4-methyl-17ot-ethyl-11- ketotestosterone, 4,17 ot-diethyhll-ketotestosterone, 4-ethyl-17a-propyl-1l-ketotestosterone, 4-propyl-17u-isobutyl- 11 ketotestosterone, 4 isopropyl-17ot-butyl-1l-ketotestosterone, 4-butyl-17tx-hexyl-ll-ketotestosterone, 4-methyl- 17w (a-methallyl) -1 l-ketotestosterone, and the like.

EXAMPLE 3 413,1 7a-dimethyl-11BJ 7,8-dihydr0xyandrostan-3-one (III) A mixture containing 0.5 gram of 4,17a-dimethyl-11flhydroxytestosterone, 55 milliliters of tertiary butyl alcohol, and milligrams of five percent palladium on charcoal as a catalyst was hydrogenated at a pressure of 15.8 pounds per square inch guage in a Parr hydrogenation apparatus. After 45 minutes the uptake of hydrogen ceased and the reaction mixture was removed from the apparatus and filtered through a diatomaceous filter aid to remove the catalyst. The filtrate was concentrated by distillation to a syrup which was dissolved in ether, again filtered and concentrated to give 0.17 gram of crystalline 43,17a-dimethyl-1 1,8, l7/3-dihydroxyandrostan-3-one (III) melting at 200 to 201 degrees centigrade. Recrystallization from methylene chloride-Skellysolve B hexanes gave 0.10 gram of a light colored crystalline solid having a melting point of 200 to 201 degrees centigrade and having a rotation of [a1 plus seven degrees in chloroform.

Analysis-Calculated for C H O C, 75.40; H, 10.25. Found: C, 74.62, 74.47; H, 10.08, 10.10.

Substituting the other 4,17u-dialkyl-1lfi-hydroxytestosterones or 4,170t-dlalkyl-1ItX-hYdI'OXYlESlOSteIOHCS of Formula I, such as for example,

4-methyl-17 a-ethyl-l IB-hydroxytestosterone, 4,17a-diethyl-1 1 fi-hydroxytestosterone, 4-propyl-17a-isobutyl-1 lfl-hydroxytestosterone, 4-isopropyl-17a-butyl-1 1 ,B-hydroxytestosterone, 4-butyl-17ot-hexyl-l l ,B-hydroxytestosterone, 4,17 ot-dimethyl- 1 1 oc-llYdl'OXYtBStOStCl'OH, 4-methyl-17u-ethyl-1lot-hydroxytestosterone, 4,17ot-diethyl-1 lot-hydroxytestosterone, 4-ethyl-17a-propyl-1 lot-hydroxytestosterone, 4-isobutyl-17ot-pentyl-1 1 ot-hydroxytestosterone,

11 as starting materials in Example. 3 above is productive of other compounds represented by Formula III, such as 45methyl-17a-ethyl-1 l5, 175dihydroxyandrostan-3 -one, 45,17a-diethyl-1 15,175-dihydroxyandrostan-3-0ne, 45-propyl-17a-isobutyl-l15,175 dihydroxyandrostan 3- one, 45-isopropyl-17a-buty1-l15,175 dihydroxyandrostan 3- one, 45-buty1-17a-hexyl-1 15,175-dihydroxyandrostan-3-one, 45,17ei-dimethyl- 1 1a, l75-dihydroxyandrostan-3 -one, 45-methyll 7a-ethyl-1 1a, l75-dihydroxyandrostan-3 -one, 45, l7a-diethy1-1 la,175-dihydroxyandrostan-3-one, 4 5-ethyl- 17 a-propyl-l 1a,175-dihydroxyandrostan-3-one, 45-is0butyl-17a-pentyl-1 lu, l75-dihydroxyandrostan-3-one,

and the like.

EXAMPLE 4 45,1 7a-dimethyI-1 75-hydroxyandrostane-3,1I-dione (IV) A mixture containing 0.5 gram of 4,17u-dimethyl-11- ketotestosterone (II), 55 milliliters of tertiary butyl alcohol and 100' milligrams of five percent palladium on charcoal as a catalyst was hydrogenated at a pressure of about fifteen pounds per square inch guage in a Parr hydrogenation apparatus. After 45 minutes the uptake of hydrogen ceased and the reaction mixture removed from the apparatus and filtered through a diatomaceous filter aid to remove the catalyst. The filtrate was concentrated by distillation to a syrup which was dissolved in ether, again filtered and concentrated to give 45,17a-dimethyl-11-ketodihydroxytestosterone (IV). The product was purified by recrystallization from methylene chloride-Skellysolve B hexane.

Substituting the other 4,17a-dialkyl-1l-ketotestosterones represented by Formula II, such as for example,

4-methyl17u-ethyll i-ketotestosterone,

4,17oc-di8thYl-l l-ketotestosterone, 4-ethyl-l7oc-propyl-1l ketotestosterone, 4-propyl-17u-isobutyl-1l-ketotestosterone, 4-isopropyll7a-butyl-1 l-ketotestosterone and 4 -butyl-17a-hexyl-1l-ketotestosterone,

as starting materials in Example 4, above, is productive of the compounds represented by Formula IV, such as for example,

45-methyl-17a-ethyl l75-hydroxyandrostane-3, l l-dione,

45,17u-diethyl-175-hydroxyandrostane-3 ,1 l-dione,

45-ethyl-17u-propyll75-hydroxyandrostane-3,1 l-dione,

45-propyl-I7u-isobutyl-175-hydroxyandrostane 3,1 l dione,

45-isopr0pyl- 17a-butyl- 175-hydroxyandrostane-3 ,1 l-dione,

45-butyl-17a-hexyll75-hydroxyandrostane-3, 1 l-dione,

and the like.

W EXAMPLE 5 4a,] 7a-dimethyl-1 15,1 75-dihydroxyandrostan- 3-0ne (III) A solution of 1.63 grams of 45,17u-dimethyl-115,l75- dihydroxyandrostan-3-one and 1.65 milliliters of absolute ethanol in 165 milliliters of chloroform is maintained at minus five to minus ten degrees centigrade for one-half vflux was continued for another 24 hours.

7 EXAMPLE 6 4 5,1 7u-dimethyl-1 -hydroxyandrostane-3,1 1 -d ione (IV) A solution is prepared containing 0.5 gram of 45,17adimethyl-115,175-dihydroxyandrostan-3-one (III), 0.5 gram of chromium trioxide, ten milliliters of glacial acetic acid and one-half milliliter of water. This mixture is stirred and maintained at room temperature for eight hours. Thereafter, excess oxidant is destroyed by the addition of methanol and the mixture is poured into fifty milliliters of ice water and the thus-obtained precipitate collected on a filter and recrystallized three times from ethyl acetate and Skellysolve B hexanes to give 45,170:- dimethyl-175-hydroxyandrostane-3,11 dione. When the compounds represented by Formula HI, such as for example, 45-methyl-17u-ethyl-115,175-dihydroxyandrostan- 3-one, 45,17a-diethyl-1 l5,175-dihydroxyandrostan-S-one, 45 ethyl-17a propyl 115,175 dihydroxyandrostan-Elone, 4a,l7ot-dimethyl-115,175dihydroxyandrostan-3-one, 4a methyl 17 a ethyl 115,175-dihydroxyandrostan-3- one, 4a-propyl-17ot-isobuty1-l15,175-dihydroxyandrostan- 3-one, 45,170: dimethyl :,175 dihydroxyandrostan- 3-one, 45-methyl-l7a-ethyl-l1a,175-dihydroxyandrostan- 3 one, 45 isopropyl 17a butyl 1 10:,175 dihydroxyandrostan-3-one, 40,17m dimethyl l1a,l75 dihydroxyandrostan-B-one, 4a-methyl- 17 u-ethyl-l 1a,175-dihydroxyandrostan-3-one and 4abutyl-l7ot-hexyl-110:,175 dihydroxyandrostan-3-one are substituted individually as starting material in Example 6 above, the process is productive of the corresponding 4,17a-dialkyl--hydroxyandrostane-3,1l-diones represented by Formula IV, such as for example, 45-methyl-17a-ethyl-175-hydr0xyandrostane 3,11 dione, 45,170: diethyl 175 hydroxyandrostane 3,11 dione, 45 ethyl 17a propyl 175 hydroxyand-rostane 3,11 dione, 40,l7m dimethyl 175- hydroxyandrostane-3,ll-dione, 4u-methyl-17m-ethyl-175- hydroxyandrostane-3,l l-dione 4a-propyl 17 isobutyll75-hydroxyandrostane-3,11-dione,45 isopropyl 17abutyl-175-hydroxyandrostane-3,ll-dione, 40c butyl 17a:- hexyl-l75-hydroxyandrostane-3,1l-dione, and the like.

EXAMPLE 7 1-dehydr0-4,17m-dimethyl-1 lp-hydroxytestosterone (V) A mixture of one gram of 4,17u-dimethyl-1lfi-hydroxytestosterone, (I) fifty milliliters of tertiary butyl alcohol, 05 milliliter of glacial acetic acid, and 0.4 gram of selenium dioxide was refluxed for 24 hours. An additional 0.4 gram of selenium dioxide was added and re- [he reaction mixture was then concentrated in vacuo to about fifteen milliliters and extracted with ethyl acetate. The ethyl acetate extract was washed with cold, dilute, aqueous ammonium hydroxide solution, cold, freshly prepared aqueous ammonium sulfide solution, again with aqueous ammonium hydroxide solution, water, and finally dilute acid. The ethyl acetate extract was then dried over sodium sulfate, filtered and evaporated to dryness giving 0.55 gram of residue containing crude 1-dehydro-4,l7adimethyl-1l5-hydroxytestosterone. The residue was dissolved in methylene chloride, adsorbed on 35 grams of synthetic magnesium silicate, and eluted with 35 milli- 4-methy1-17a-ethyl-1 1 fi-hydroxytestosterone, 4,17a-diethyl-1 1 p-hydroxytestosterone, 4-propyl-17a-isobutyl-1 1 B-hydroxytestosterone, 4-methyl- 17 u-( u-methallyl) -1 1 u-hydroxytestosterone, 4,17a-dimethyl-1 lu-hydroxytestosterone, 4-methyl-17a-ethyl-1 la-hydroxytestosterone, 4-butyl-17a-pentyl-1 la-hydroxytestosterone, 4-methyl-17m-( a-methallyh 1 1 a-hydroxytestosterone, 4, 17a-dimethyl-1 1 -ketotestosterone, 4-methyl-17a-ethyl- 1 l-ketote stosterone, 4-isopropyl-17a-buty1-1 l-ketotestosterone, and 4-methyl-17au-methallyl) -1 l-ketotestosterone,

Example 6 above is productive of the corresponding l-dehydro compounds represented by Formulae V and VI, such as 1-dehydro-4-methy1-17a-ethyl- 1 1 fi-hydroxytestosterone, 1-dehydro-4,17a-diethyl-1 1 fi-hydroxytestosterone, 1'dehydro-4-propy1-17a-isobuty1-1 IB-hydroxytestosterone, l-dehydro 4 methy1-17a-(a-methal1yl) 11p hydroxytestosterone, 1-dehydro-4,17a-dimethyl-1 IOC-hYdI'OXYtGStOStCI'OIlC, 1-dehydr0-4-methyl-17u-ethyl-1 lot-hydroxytestosterone, 1-dehydro-4-butyl-17a-pentyl-1 la-hydroxytestosterone, l-dehydro 4 methyl-17u-(a-methallyl) 11oz hydroxytestosterone, 1-dehydro-4,17a-dimethy1-1 l-ketotestosterone, 1-dehydro-4-methyl-17a-ethyl-1 l-ketotestosterone, 1-dehydro-4-isopropyl-17a-buty1-1 l-ketotestosterone, 1-dehydro-4-methyl-17a (a methallyl) 11 ketotestosterone, and the like.

It is to be understood that the invention is not to be limited to the exact details shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A 4,17a-dialkyl-1lfi-hydroxytestosterone represented by the following formula:

OH ----R on i alkyl wherein R is an aliphatic hydrocarbon radical containing from one to six carbon atoms, inclusive, and wherein alkyl is a lower-alkyl radical containing from one to four carbon atoms, inclusive.

2. 4,17a-dimethyl-1lfi-hydroxytestosterone.

3. 4a,17a dimethyl 115,175 dihydroxyandrostan- 3-one.

4. 4a,17a dialkyl 115,17/3 dihydroxyandrostan 3- one wherein the 4-alky1 substituent is a lower-alkyl radical containing from 1 to 4 carbon atoms, inclusive, and the 17-a1ky1 substituent is an alkyl radical containing from 1 to 6 carbon atoms, inclusive.

References Cited in the file of this patent UNITED STATES PATENTS 2,660,586 Murray et a1 Nov. 24, 1953 2,678,933 Meister May 18, 1954 2,695,907 Murray Nov. 30, 1954 2,697,110 Murray Dec. 14, 1954 2,735,854 Herr Feb. 21, 1956 2,766,264 Bernstein Oct. 9, 1956 2,837,464 Nobile June 3, 1958 2,838,533 Ralls June 10, 1958 2,842,570 Herr July 8, 1958 2,844,602 Ringold et al. July 22, 1958 2,864,831 Eppstein et al. Dec. 16, 1958 2,864,832 Eppstein et a1. Dec. 16, 1958 2,881,191 Herr Apr. 7, 1959 UNITED :STATES- PATENT. OFFICE CERTIFICATE OF CORRECTION Patent No, 2,990 4l6 June. 27, 1961 Raymond L Pederson et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, line 36, for dioxode" read dioxide column 4-, line 62, for "2,L-dimthyl-f? read QA-dimethylcolumn 8, line 8, for ethylisolvaleric" read a-ethylisovaleric column l3. line 18 for "-ll read Signed and I sealed this 23rd day of January 1962.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Off Commissioner of Patents 

1. A 4,17 A-D-ALKYL-11B-HYDROXYTESTOSTERERONE REPRESENTED BY THE FOLLOWING FORMULA: 